Therapeutic agents



5 their systemic efiects.

Patented June .193 9 Hynson, Westcott &-' Dunning, Incorporated,Baltimore, Md., a corporation of Maryland No Drawing.

Application June 1'1, 1938, Serial No. 214,344

3 Claims. (01. 167 65) This invention relates to alkyl nitrites havingpharmacological and clinical activity andbeing otherwise suitable foruse as therapeutic agents, particularly as vaso dilators. Certain alkylnitrites such as ethyl nitrite and amyl nitrite are'known and have beenused as vaso dilators. nitrites of alkyls having less than six carbonatoms, are quite unstable chemically, uncertain ill in theirphysiological action and unpleasant and unsafe to use therapeutically. Ihave found that they are relatively more toxic and irritating than thehigher alkyl nitrites and produce undesired effects on theoxy-hemoglobin when used in anii5 mals. On the other hand I have foundthat alkyl nitrites in which the alkyl group contains more than twelvecarbon 'atoms have practically no vapor pressure and for this reason arenot suit.-

able for therapeutic use because they cannot be 20 administered byinhalation.

In the course of my investigation I have foun that alkyl nitritescontaining from six to twelve carbon atoms in the alkyl group and moreespecially those containing from six to ten carbon atoms arepharmacologically active and. give results of quite a difierentcharacter from those produced by the lower alkyl nitrites, exemplifiedby a' striking lack of toxicity and absence of detrimental effect onoxy-hemoglobin; The

compounds tend tobecome less active pharmacologically as the number ofcarbon atoms in the alkyl group increases above eight and, as indicatedabove, twelve carbon atoms in the alkyl group represents a practicalupper limit.

35 The properties of the alkyl nitrites having six to twelve carbonatoms which are believed to be principally responsible for theirclinical utility are their low but .substantial volatility, theirchemical'stability and their lipoid solubility. If

40 the compounds were not volatile theyqould not be administered byinhalation. 0n the other hand, if the compounds were too volatile theywould be too readily and quickly exhaled from the lungs and would haveless chance to exert Moreover high volatility favors high concentrationin the blood which is objectionable. Their lipoid'solubility insuresthat they will be removedfrom the blood stream by absorption into thefatty tissue and lipoid- 50 like substances in the body therebyproducing their effects, for example, on the walls of the blood vessels.If they were not soluble in or absorbed by the tissue ofthe body, theywould concentrate in the blood stream and exert their 55 toxic effectand detrimental action on the blood These lower alkyl nitrites, i. e.,

1 nor more than twelve.

and they would be lost by exhalation more quickly. Their chemicalstability, of course, is associated with their low toxicity. Owing totheir low volatility and high lipoid solubility, their sojourn in theblood stream is shortened, their toxicity is reduced and their depressoraction is prolonged. Shortening thesojourn of the compounds in the bloodstream obviates the formation of toxic by-products such asmet-hemoglobin.

The compounds embraced by my invention may be represented by the generalformula:

in which nis a whole number not less than six l5 They are generallycharacterized as straw colored oily liquids possessing a characteristicodor and a specific gravity somewhat less than that of water. They arechemically stable at atmospheric temperatures but decompose slowly underthe influence of direct sunlight presumably liberating nitric oxide.They are very slightly soluble in water, soluble in the common organicsolvents and readily soluble in lipoidal material.

The following example illustrates the preparation of the octyl nitrite:

172 cc. of 2-ethyl hexanol-lis added to a mixture of 1100 cc. of waterand 110 cc. of concentrated hydrochloric acid and cooled at 0 C. Asolution of 110 grams of sodium nitrite in 500 cc. of water is added tothis mixture drop by drop with mechanical stirring and at such a ratethat the temperature is. kept below 10f C. After all the solution hasbeen addedpstirring is continued until practically all the blue' colorhas disappeared from the lower layer. The two layers are separated andthe octyl nitrite is dried with anhydrous sodium sulfate or othersuitable drying agents. It is then filtered and distilled under reducedpressure. The boiling is plus or minus 55 C. at 8-10 mm. Analysis of thefinished product from several batches has shown it to vary from 94% to96% octyl nitrite.

The nitrites of other alkyls may be similarly prepared.

The properties of the compounds have been determined by pharmacologicaland clinical tests. Their efiect on coronary vessels has been determinedby (1) perfusion of the coronary vessels of the isolated rabbits heart(2) use of the coronary rings of the steer and (3) the Moravitz and Zahnexperiment on the dog in situ. 'By

these" methods various compounds were compared and their degree ofprolonged depressor activity and the rapidity of the return subjects tonormal was ascertained.

In addition, the acute toxicity by inhalation and injection wasdetermined using white male rats. Subacute toxicity was also determinedby both of these methods on rats. Furthermore, the eifect uponhemoglobin was studied in the living animal. All o'fthese experimentswithnitrites of the group defined above, and particularly octyl nitrite,have demonstrated their unusual pharmacological properties. I haveproved that they possess the properties of rapid and prolonged actioncoupled with low toxicity. I have found,

or the furthermore, that they produce no deleterious action on the bloodand do not form met-hemoglobin as do alkyl nitrii'es of low molecularweight. Experimental observation with human subjects has demonstratedthat duration of the depressor response produced by these compounds,particularly octyl nitrite, is six to seven times that obtained withamyl nitrite, even though much smaller doses are used. Clinicalexperimentation by others has proved that these compounds are useful inconditions where depressor activity or lowering of the blood pressure isindicated, such as asthma, angina pectoris paroxysmal hypertension, orotherspams associated with the constriction of blood vessels. I havefound that the most suitable method of application of these compounds isby inhalation,

I claim:

l. A vasodilator comprising an alkyl nitrite the formula CaHrzNOz.

2. 'A vasodilator comprising octyl nitrite.

3. A vasodilator comprising-ethyl hexyl nitrite.

JOHN C. KRANTZ, JR.

